First Anti–PD-1 Immunotherapy, Pembrolizumab, Receives Accelerated FDA Approval for Advanced Melanoma
On September 4, 2014, the FDA approved the first anti–programmed death receptor (PD)-1 therapy pembrolizumab (Keytruda; Merck) for the treatment of patients with unresectable or metastatic melanoma and disease progression after therapy with ipilimumab, or, for a patient with BRAF V600 mutation, after a BRAF inhibitor therapy. The approved dosing schedule for pembrolizumab is 2 mg/kg every 3 weeks.
The FDA applied its accelerated process for this approval based on early clinical data showing tumor reductions and durability of response. Ongoing phase 2 and 3 clinical trials are expected to provide confirmatory information to demonstrate clinically meaningful benefits, including potential improvement in survival and/or reduction in disease progression.
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first ever anti–PD-1 therapy to receive FDA approval. The FDA granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the early results from the ongoing multicenter, open-label, randomized, dose-comparative study of the KEYNOTE-001 phase 1b trial with 173 patients with unresectable or metastatic melanoma and progression of disease.
All patients had received previous treatment with ipilimumab and a BRAF or a MEK inhibitor for patients who had a BRAF V600 mutation. The patients were randomized to 2 mg/kg (N = 89) or to 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression.
Early results in the 89 patients who received pembrolizumab 2 mg/kg every 3 weeks showed an overall response rate of 24% (95% confidence interval [CI], 15-34), including 1 complete response and 20 partial responses. At the time of the analysis, 86% (N = 18) of patients with objective responses had ongoing responses, with duration of response ranging between 1.4 and 8.5 months. Most patients showed continued response after that.
Severe immune-mediated adverse events were uncommon. Pembrolizumab was discontinued because of adverse events in 6% of 89 patients receiving the recommended dose and in 9% of 411 patients across all doses. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab. The most common serious adverse events reported in ≥2% of patients included renal failure, dyspnea, pneumonia, and cellulitis. The most common (≥20% of patients) adverse events were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.
Ibrutinib Received Expanded Indication for Patients with CLL and 17p Deletion
On July 28, 2014, the FDA issued an expanded indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a deletion in chromosome 17 (17p deletion), which results in poor response to standard CLL therapies. Earlier in the year, the FDA approved ibrutinib for all patients with CLL, after having designated it as a breakthrough therapy.
With this new indication, the FDA also approved new labeling for the drug to reflect that the clinical benefit of ibrutinib for the treatment of CLL has been verified based on new clinical trial results. These results confirmed the progression-free survival (PFS) and overall survival (OS) benefits associated with ibrutinib.
The expanded indication for patients with 17p deletion is based on results from a clinical trial of 391 previously treated patients with CLL; of these, 127 patients had CLL with 17p deletion. Patients were randomized to ibrutinib or to ofatumumab until disease progression or until side effects became intolerable.
The trial was stopped early after a preplanned interim analysis showed that patients receiving ibrutinib had a 78% PFS improvement and a 57% OS benefit. Among the 127 patients with CLL plus 17p deletion, those receiving ibrutinib had a 75% improvement in PFS.
The most common side effects associated with ibrutinib were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and fever.
This new indication was approved under the FDA’s accelerated approval and was reviewed under the agency’s priority review program.
FDA Approved Idelalisib for Three Types of Hematologic Cancers
On July 23, 2014, the FDA approved idelalisib (Zydelig; Gilead Sciences) for the treatment of patients with relapsed chronic CLL to be used in combination with rituximab (Rituxan). Idelalisib is recommended for use in this patient population in those for whom rituximab alone would be considered inappropriate therapy because of potential comorbidities. The drug received a breakthrough therapy designation for CLL earlier this year.
On the same day, the FDA granted idelalisib an accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL), as well as relapsed small lymphocytic lymphoma (SLL). Idelalisib is intended to be used in patients who have received at least 2 previous systemic therapies.
Idelalisib’s safety and effectiveness for relapsed CLL were established in a clinical trial of 220 patients with this condition who were randomized to receive idelalisib plus rituximab or to placebo plus rituximab. The trial was stopped after the first prespecified interim analysis point, which showed that the active combination resulted in a PFS of 10.7 months compared with approximately 5.5 months with rituximab plus placebo. Results from a second interim analysis continued to show a statistically significant improvement for the active combination.
The safety and effectiveness of idelalisib in the treatment of FL and relapsed SLL were established in a clinical trial with 123 patients with indolent non-Hodgkin lymphomas. All patients received idelalisib and were evaluated for objective response rate (ORR). Results showed a 54% ORR in patients with relapsed FL and a 58% ORR for patients with SLL.
Idelalisib carries a Boxed Warning regarding the risk of fatal and serious toxicities, including liver toxicity, colitis, pneumonitis, and intestinal perforation. The drug was also approved with a REMS (Risk Evaluation and Mitigation Strategy) program.
Common side effects with idelalisib include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.
Belinostat Approved for Peripheral T-Cell Lymphoma, an Aggressive Form of NHL
The FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) on July 3, 2014, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The approval was done under the agency’s accelerated approval program. PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. PTCL represents approximately 10% to 15% of NHL cases in North America.
Belinostat works by preventing the development of T-cells from becoming cancerous. According to Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, “This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma.”
The safety and effectiveness of belinostat were evaluated in a clinical trial involving 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or until their side effects became unacceptable. In all, 25.8% of the patients showed complete or partial response after treatment with belinostat.
The most common side effects seen with belinostat were nausea, fatigue, fever, anemia, and vomiting.
Belinostat was designated by the FDA as an orphan drug, because it is intended for the treatment of patients with PTCL, which is a rare disease.
Lymphoseek Injection Received Expanded Indication for Head and Neck Cancer SLN Biopsy
Technetium Tc 99m tilmanocept (Lymphoseek Injec-tion; Navidea Biopharmaceuticals) received an expanded indication by the FDA on June 13, 2014, for guiding sentinel lymph node (SLN) biopsy in patients with head and neck cancers with squamous-cell carcinoma of the oral cavity. This is the first approval for a radiopharmaceutical agent for the diagnosis of SLN. The approval was done under the agency’s priority review process.
In 2013, the FDA approved Tc 99m for lymphatic mapping in patients with breast cancer or with melanoma. The new indication was approved based on data from a prospective phase 3 study showing that Tc 99m had a significantly greater ability to correctly identify patients with pathology-positive SLN compared with lymph node dissections or pathologic evaluations.
In addition, the use of multiple levels of lymph node dissection in the trial resulted in the removal of 38 lymph nodes per patient compared with only 4 lymph nodes, on average, with Tc 99m, which represents a substantial reduction in potential morbidity in patients undergoing SLN biopsy.